Central synaptopathy is the most conserved feature of motor circuit pathology across spinal muscular atrophy mouse models

Jannik M Buettner; Josiane K Sime Longang; Florian Gerstner; Katharina S Apel; Beatriz Blanco-Redondo; Leonie Sowoidnich; Eva Janzen; Tobias Langenhan; Brunhilde Wirth; Christian M Simon

doi:10.1016/j.isci.2021.103376

Central synaptopathy is the most conserved feature of motor circuit pathology across spinal muscular atrophy mouse models

iScience. 2021 Oct 30;24(11):103376. doi: 10.1016/j.isci.2021.103376. eCollection 2021 Nov 19.

Affiliations

¹ Carl-Ludwig-Institute for Physiology, Leipzig University, Leipzig 04103, Germany.
² Rudolf Schönheimer Institute of Biochemistry, Division of General Biochemistry, Medical Faculty, Leipzig University, Leipzig 04103, Germany.
³ Institute of Human Genetics, Center for Molecular Medicine Cologne, Institute for Genetics, University of Cologne, Cologne, Germany.
⁴ Center for Rare Diseases Cologne, University Hospital of Cologne, Cologne, Germany.

Abstract

Spinal muscular atrophy (SMA) is a neurodegenerative disease caused by reduced survival motor neuron (SMN) protein. Recently, SMN dysfunction has been linked to individual aspects of motor circuit pathology in a severe SMA mouse model. To determine whether these disease mechanisms are conserved, we directly compared the motor circuit pathology of three SMA mouse models. The severe SMNΔ7 model exhibits vast motor circuit defects, including degeneration of motor neurons, spinal excitatory synapses, and neuromuscular junctions (NMJs). In contrast, the Taiwanese model shows very mild motor neuron pathology, but early central synaptic loss. In the intermediate Smn ^2B/- model, strong pathology of central excitatory synapses and NMJs precedes the late onset of p53-dependent motor neuron death. These pathological events correlate with SMN-dependent splicing dysregulation of specific mRNAs. Our study provides a knowledge base for properly tailoring future studies and identifies central excitatory synaptopathy as a key feature of motor circuit pathology in SMA.

Keywords: Molecular biology; Molecular neuroscience; Neuroscience.